Lysophosphatidic acid (LPA, 1-radyl-sn-glycerol-3-phosphate) elicits growth factor-like effects in almost every cell type. At the organ system level, LPA is implicated in complex physiological responses that include immunological competence, brain development, wound healing, coagulation, and regulation of blood pressure. The pleiotropic physiological functions of LPA suggest that LPA could contribute to a number of pathophysiological states including cancer, atherosclerosis, hypertension, ischemia reperfusion injury, diabetes, cardiovascular diseases, stroke, prevention of toxicity of chemotherapy and radiation therapy, immunomodulation and others.
LPA can be produced either extracellularly or intracellularly in response to various stimuli including growth factors, LPA itself, phorbol esters, and epidermal growth factor (EGF). In the course of blood coagulation, LPA is mainly generated sequentially by two enzymatic reactions. First, the action of phospholipase A1 and A2 (PLA) on phosphatidylcholine (PC) yields lysophosphatidylcholine (LPC). Second, the lysophospholipase D (lysoPLD) activity of autotaxin (ATX) converts LPC to LPA. ATX is one of the forty most upregulated genes in invasive cancers, and has been implicated in cell motility and tumor invasion, metastasis, and neovascularization. LPA signals through the activation of specific receptors which in turn leads to distinct cellular events depending in the receptor subtype expressed by the targeted cell. Cell surface LPA receptors belong to the membrane G protein-coupled receptors (GPCR) protein family. There are five different LPA GPCR characterized on the surface of mammalian cells: LPA1, LPA2, LPA3, LPA4 and LPA5. The first three were formerly called endothelial differentiation genes (EDG), EDG2, EDG4, EDG 7, whereas GPR23/P2Y9 and GPR92, tentatively designated as LPA4 and LPA5 respectively, are members of the purinergic cluster in the GPCR superfamily. Cancer cells of different cellular origins express LPA GPCR subtypes in LPA1 in differing amounts; however, LPA1 is the most widely expressed in almost every cancer cell type, whereas, LPA4 seems to be expressed at very low levels. Ovarian and breast cancer cells express multiple isoforms of the LPA GPCRs and LPA accumulates in tumor cell ascites and in tumor cell effusates. LPA also activates the nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ). Through activation of these GPCRs and PPARγ, LPA regulates multiple physiological and pathological responses.
The involvement of LPA receptors in many pathophysiologies have implicated them as attractive targets for therapeutic intervention. As with many other GPCRs; LPA receptors should be amenable to the development of highly specific and potent agonists or antagonists that have favorable pharmacokinetic, bioavailability, and metabolic characteristics. Currently available compounds represent a promising but limited start to the development of useful chemical tools, although none can be considered definitive in determining receptor selectivity or biological functions, especially for studies in vivo. The development of more selective, more stable, more potent, and more drug-like agonists and antagonists is eagerly awaited, and has been a bottleneck in therapeutic exploration.